There are an estimated 8,000 to 10,000 new cases of spinal cord injury in the United States each year. While most victims survive, virtually all are left with partial to permanent paralysis and limited prospects for improvement. Although work in recent years has vastly improved our understanding of the molecular and cellular biology of the healing process following spinal cord injuries, translation of these findings to practical, clinical use has been limited. We propose to apply the tools of peptide and polymer chemistry to construct a highly well-defined polymeric matrix that will support neural tissue regeneration in the injured spinal cord. This growth matrix will be not only biocompatible, but bioactive - tailored at the molecular level with specific growth cues to provide functional assistance to tissue regeneration. Specifically, the aims of this proposal are (1) chemical synthesis of human neurotrophin-3 (NT-3), a key growth factor involved in axonal regrowth; (2) preparation of an MMP-degradable hydrogel that will allow for covalent attachment of a suitably functionalized NT-3 analogue; (3) construction of the resulting bioconjugate; and (4) optimization of the performance of the NT-3-grafted hydrogel using combinatorial synthesis techniques coupled with in vitro assays. We envisage that the initial studies described herein will serve as the foundation for further studies in our laboratory in the design and chemical synthesis of biomimetic tissue regeneration matrices.